Process for preparing 1,3,5(10),6,8-pentaene steroids and intermediates

ABSTRACT

PROCESS FOR PREPARING 1,3,5(10),8,11-PENTAENE AND 1,3,5(10),6,8-PENTAENE STEROIDS FROM 1,3,5(10),9(11)-TETRAENE STEROIDS USING A BENZOQUINONE STEP FOLLOWED BY A DEHYDROGENATION-HYDROGENATION SEQUENCE. THE 1,3,5(10), 8,11-PENTAENES ARE NEW AND USEFUL AS ESTROGENIC AGENTS AND INTERMEDIATES. OTHER USEFUL INTERMEDIATES DESCRIBED ARE NOVEL 12A-HYDROXY (ALKOXY)-1,3,5(10),9(11)-TETRAENE STEROIDS. THE OVERALL CONVERSION OF $9(11)-ESTRONE TO EQUILENIN IS ILLUSTRATED AS REPRESENTATIVE OF THE INVENTION.

United States Patent 3,707,490 PROCESS FOR PREPARING1,3,5(),6,8-PENTAENE STEROIDS AND INTERMEDIATES John A. Edwards, LosAltos, and Jack Ackrell, Mountain View, Calif., assignors to SyntexCorporation, Panama, Panama No Drawing. Filed Apr. 27, 1970, Ser. No.32,367 Int. Cl. C07c 169/08 US. Cl. 260397.45 24 Claims ABSTRACT OF THEDISCLOSURE Process for preparing 1,3,5(10),8,11-pentaene and1,3,5(10),6,8-pentaene steroids from 1,3,5( 10) ,9( ll )-tetraenesteroids using a benzoquinone step followed by adehydrogenation-hydrogenation sequence. The 1,3,5(10), 8,11-pentaenesare new and useful as estrogenic agents and intermediates. Other usefulintermediates described are novel12a-hydroxy(alk0xy)-l,3,5(10),9(11)-tetraene steroids. The overallconversion of A -estrone to equilenin is illustrated as representativeof the invention.

The present invention relates to a new process in steroid chemistry andto new compounds prepared in accordance with said process.

More particularly, the present invention is directed to a new processuseful for preparing new 1,3,5(10),8,11- pentaene steroids and1,3,5(10),6,8-pentaene steroids, e.g., equilenin, from the corresponding1,3,5(10,9(11)- tetraene steroids, e.g. A -estrone. It is furtherdirected to new 12a-hydroxy(alkoxy)-l,3,5(10),9(11)-tetraeneintermediate compounds prepared when practicing the aforementionedprocess.

The present invention can be depicted as follows:

In the above formulas,

R is hydrogen or lower alkyl;

R is hydroxy or a conventional ester or ether thereof;

R is hydroxy or a conventional ester or ether thereof;

R is hydrogen, alkyl of 1 to 3 carbon atoms, alkenyl of 1 to 3 carbonatoms, or alkynyl of 1 to 3 carbon atoms; or

R and R taken together are an oxo group.

The present invention in a first, principal aspect is directed to aprocess which comprises treating an estra- 1,3,5 (10),9(1l)-tetraenesteroid (I) with a benzoquinone to prepare the correspondingestra-l,3,4(10),8,11-pentaene steroid (III).

The present invention in a second, principal aspect is directed to aprocess which comprises treating an estra- 1,3,5 (10),9(11)-tetraenesteroid (I) with a benzoquinone to prepare the correspondingestra-l,3,5(l0),8-11-pentaene steroid (III) and converting the latter tothe corresponding estra-1,3,5(10),6,8-pentaene steroid (IV) with adehydrogenation-hydrogenation sequence.

The reaction (I- III) is favored when employing anhydrous orsubstantially anhydrous conditions. When the reaction is conducted underaqueous conditions or in the presence of a primary or secondary loweralkanol, the 12a-hydroxy and -lower alkoxy intermediates (II) arerespectively formed in predominant proportion to compound (III).Intermediate compound (II) slowly converts to the corresponding compound(III) in the reaction mixture or it can be isolated via conventionaltechniques. The conversion of (II) to (III) in the 12a-alkoxy series, isfavored by conducting the reaction (I)- (III) under acidic conditions,such as can be provided by dilute acid, i.e., a dilute solution of amineral or carboxylic acid, e.g., oxalic acid.

After isolation, if desired, the 12a-hydroxy(alkoxy) compound (II) canbe converted, if desired, to compound (III) with a separate dilute acidtreatment step. Said acid can be a dilute solution of mineral acid orcarboxylic acid, preferably oxalic acid. The acid treatment step isconveniently conducted in inert liquid organic reaction media or theacid per se, particularly if a liquid organic carboxylic acid isemployed. It is further conducted at temperatures ranging from about 25to about preferably at reflux.

The principal reaction (I III) is conveniently conducted in inert liquidorganic reaction media and at temperatures ranging from about 0 to about50 C. and for a period of time ranging from about 15 minutes to about 3hours. Although the reaction proceeds using any proportion of reactants;in the preferred embodiments, from about 1.1 to about 1.5 moles of thebenzoquinone is employed per mole of starting compound. As mentionedabove, the reaction is preferably conducted under acidic conditions whenemploying a lower alkanol so as to proceed through the 12u-alkoxyintermediate (II).

After the reaction, the product compound (III) can be isolated andrecovered via usual, conventional techniques, such as crystallization,filtration, decantation, and chromatography.

Thereafter, the 1,3,5 (10),8,11-pentaenes (III) are treated in adehydrogenation-hydrogenation sequence comprising dehydrogenation withpalladium catalyst followed by exposure to hydrogen to yield thecorresponding 1,3,5(10),6,8-pentaenes (IV). Thisdehydrogenationhydrogenation sequence is conveniently conducted in inertliquid organic reaction media such as toluene, benzene, mesitylene,etc., followed by conventional recovery procedures.

With further reference to the above reaction sequence, the compoundsrepresented by Formulas II and [II are novel compounds of the presentinvention. These compounds are useful as intermediates, as hereindescribed, for the preparation of compounds (IV). In addition, thecompounds of Formula III are useful estrogenic agents in the estrogenreplacement therapy and for the control and regulation of fertility.

The product compounds (IV) are known compounds and are useful and havebeen used as estrogenic agents. As such, compounds (III) and (IV) can beadministered and used in the same manner as other estrogenic agents areused, such as mestranol.

The estra-1,3,5(),9(l1)-tetraene starting compounds of the presentinvention are known and can be prepared in accordance with knownprocedures. US. Pat. 3,385,872 describes some of these startingcompounds. If desired, a 17-oxo starting compound can be utilized in theprocess of the present invention, as described above. Upon reaction end,the products can be further elaborated at the C-3 and 017 positions. Forexample, the C-3 hydroxy group can be conventionally esterified oretherified. In accordance with known procedures, the l7-oxo group can bereduced or treated with organo metallic reagents. The resultant17fl-hydroxyl can be conventionally esterified or etherified.

In the present specification and claims, the term lower alkyl refers toand denotes a primary or secondary straight chain saturated hydrocarbongroup containing from 1 to 6 carbon atoms and 1 and 2 and 3 and 6 carbonatoms and 1 to 2 to 3 to 6 carbon atoms.

Suitable benzoquinones for the purpose of the present invention includethe orthoand parabenzoquinone which can be unsubstituted or substitutedwith one or more groups, notably acyl and cyano and halogen, including,in the latter category, bromo, ch'loro, and fluoro. Typicalbenzoquinones include 1,2-benzoquinone,

l ,4-benzoquinone, 2,3-dichloro-5,6-dicyano-l ,4-benzoquinone,tetrachloro- 1 ,Z-benzoquinone, 2,3-difluoro-1,4-benzoquinone,2,3-dibenzoyl-1,4-benzoquinone, 2,3-dicyano-1,4-benzoquinone,tetrachloro-1,4-benzoquinone, 2,3-difiuoro-1,2-benzoquinone,2,3-dicyano-1,Z-benzoquinone,

and the like. Preferred are those benzoquinones with an oxidationpotential of about 0.9 and higher, for example,

tetrachloro- 1 ,Z-benzoquinone, 2,3-difluoro-1,4-benzoquinone,

2 ,3-dicyano- 1 ,4-benzo quinone, 2,3-dibenzoyl-1,4-benzoquinone, and2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ The expressionconventional hydrolyzable esters and ethers as used herein refers tothose physiologically acceptable hydrolyzable ester groups and labileether groups conventionally employed in the pharmaceutical are such asacetate, propionate, butyrate, trimethylacetate, valerate,methylethylacetate, caproate, t-buylacetate, 3- methylpentanoate,enanthate, caprylate, triethylacetate, pelargonate, decanoate,undecanoate, benzoate, phenylacetate, diphenylacetate,cyclopentylpropionate, methoxyacetate, aminoacetate,diethylaminoacetate, trichloroacetate, B-chloropropionate,bicyclo[2.2.2]octane-l-carboxylate, adamantoate, dihydrogen phosphate,dibenzyl phosphate, sodium ethyl phosphate, sodium sulfate, sulfate,tetrahydropyran-Z-yl ether, tetrahydrofuran-2yl ether, 4-rnethoxytetrahydropyran-4-yl, cyclopentyl ether and the like.

Suitable insert liquid organic reaction media for the purposes of thepresent invention include the usual compounds conventionally employed assolvents such as the aromatics, e.g. benzene and toluene; the ethers,e.g. tetrahydrofuran, dioxane and diethyl ether; the ketones, e.g.acetone; ethylene glycol and propylene glycol ethers, e.g. monoglyme anddiglyme; and so forth.

In other embodiments of the present invention, the 12a-hydroxyand -lower-alkoxy-1,3,5 10 ,9( 1 1 )-tetraene compounds (II) can be hydrogenated,such as with platinum catalyst in inert, liquid reaction media, toprepare the corresponding l2a-hydroxyand -lower alkoxy-l,3,5 (10)-trienecompounds.

The following examples serve to further typify the manner by which thepresent invention can be practiced and represent, in one aspect, thebest mode for carrying out the invention. As such, however, they shouldbe construed merely as illustrative and not as limitative upon theoverall scope hereof.

EXAMPLE 1 A solution of 3-methoxyestra-1,3,5(l0),9(11)-tetraen- 17-one(300 mg.) in ml. of benzene is stirred at room temperature. To thestirred solution is added a solution of 360 mg. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone which is dispersed in 100 ml.of benzene. The anhydrous mixture is allowed to stand at roomtemperature overnight and is then filtered through a column of alumina.The filtrate is subjected to preparative thin layer chromatography onsilica gel, impregnated with silver nitrate to provide the3-methoxy-estra-l,3,5(10),8,1l-pentaen-17- one product which can berecrystallized from methanol.

In a similar manner, the foregoing procedure can be practiced uponstarting compounds bearing alternate C-3 ethers and C-3 esters as wellas the corresponding C-17a elaborated C-l75 hydroxy, ethers, or estersso as to prepare the corresponding 1,3,5 (10),8,11-pentaene compoundsbearing the respective substituents at the C-3, 17 positions, forexample,

3-methoxyestra-l ,3,5( 10) ,8,1 1-pentaen-17p-o1,

3-methoxy-17a-methylestra-l ,3 ,5(10),8,l1-pentaen-3-methoxy-17a-ethylestra-l,3,5(10),8,l l-pentaen-17fi- 01, and

3-methoxy-17u-ethynylestra-1,3 ,5( 10) ,8,1 l-pentaen- EXAMPLE 2 Asolution of 100 mg. of 3-methoxyestra-1,3,5(l0), 9( l1)-tetraen-l7-onein 20 ml. of a 5% aqueous dioxane solution is prepared at roomtemperature. To this solution is added a solution of mg. of2,3-dichloro-5,6-dicyano- 1,4-benzoquinone in 20 ml. of dioxane. Afterallowing the resultant mixture to stand at room temperature for about 10minutes, 100 ml. of ethyl acetate are added and the resultant mixturepoured into water. The resultant mixture is then extracted with sodiumbicarbonate and the filtrate subjected to preparative thin layerchromatography to provide the 3 methoxy-1,3,5(10),8,11-pentaen- 17-oneand 3 methoxyestra 1,3,5 (10),9(11) tetraen- 12a-ol-17-one products.

In a similar manner, the foregoing procedure can be practiced upon theother C-3,17 elaborated compounds of the present invention so as toprepare the corresponding 1,3,5(10),8,ll-pentaene andl2a-hydroxy-l,3,5(l0), 9(l1)-tetraene products, for example,3-methoxyestra-1,3,5 10) ,8,1 1-pentaen-17/8-ol,3-methoxy-17a-methylestra-1,3,5 10 ,8,l l-pentaen- 176-01,3-methoxy-l7a-ethylestra-l,3,5(10),8,1l-pentaen- 17,8-01, and3-methoxy-17a-ethyny1estra-1,3,5 l0),8,1 l-pentaen- 175-01, and3-methoxyestra-l,3,5(10),9(11)-tetraene-12u,17{3-diol,3-methoxy-17a-methylestra-1,3,5(10),9(11)-tetraene- 12a,17,B-diol,3-methoxy-17a-ethylestra-1,3,5(10),9(11)-tetraenel2ot,17fl-diol, and3-methoxy-17a-ethynylestra-1,3,5( 10),9(1 l )-tetraene- 120:,17fi-di01.

EXAMPLE 3 To a solution of 1 gram of 3-methoxyestra-1,3,5(l0),9(1l)-tetraen-17-one in 100 ml. of 3% methanolic benzene containing 0.5%p-toluene sulfonic acid are added 1.1 grams of2,3-dichloro5,6-dicyano-1,4-benzoquinone in 100 ml. of 3% methanolicbenzene. The resultant solution is stirred at room temperature for aperiod of 1 hour. After this time, the resultant solution is extractedwith aqueous sodium hydroxide solution and the benzene solution filteredthrough alumina to provide the3-methoxyestra-1,3,5(10),8,1l-pentaen-17-one and 3,12u-dimethoxyestra1,3,5 10),8,11 pentaen 17 one products which can be recrystallized frommethanol.

In a similar manner, the corresponding C-3,17 elaborated compounds ofthe present invention corresponding to the product identified in theforegoing procedure can be prepared utilizing the appropriate startingmaterials, for example,

3-methoxyestra- 1 ,3 ,5 10) ,8, 1 l-pentaen- 17 5-01, 3-methoxy-17a-methylestra- 1,3,5 l ),8, 1 l-pentaen- 17 -01,3-methoxy-17u-ethy1estra-1,3,5(10),8,11-pentaen-175-o1, 3-methoxy-17a-ethynylestra-1,3,5(10),8,1l-pentaen- 175-01,3,l2a-dimethoxyestra-1,3 ,5(l0),9(11)-tetraen-175-ol, 3,12a-dimethoxy-17a-methy1estra-1,3,5(10),9(11)- tetraen- 175-01,3,12a-dimethoxy-17u-ethylestra-1,3,5(10),9(11)- tetraen-175-o1, and3,12a-dimethoxy-l7a-ethynylestra-1,3,5(10),9(11)- tetraen- 17 5-01.

EXAMPLE 4 A solution of mg. of 3-methoxyestra-1,3,5(10),9(11)-tetraen-12a-ol-17-one in 5 ml. of benzene and 3 mg. of oxalic acidis heated to the boiling point and maintained under reflux for 15minutes with stirring. After this period, the solution is allowed tocool to room temperature and then filtered through a column of silicagel to provide the 3-methoxyestra-1,3,5(10),8,11-tetraen-17- one productwhich can be recrystallized from methanol.

In a similar manner, the C-3,17 elaborated products of Example 2 can besubjected to the foregoing procedure so as to prepare the corresponding1,3,5 (10),8,11-pentaene products i.e., 3 methoxyestra 1,3,5(10),8,1l-pentaene 175 ol, 3 methoxy 17oz methylestra-1,3,5(10), 8,11pentaen 175 ol, 3 methoxy 17a ethylestra- 1,3,5(10),8,11-pentaen-175-ol, and so forth.

EXAMPLE 5 A solution of 100 mg. of the 3,12a-dimethoxyestra- 1,3,510),9-tetraen-17-one in ml. of benzene and 10 mg. of oxalic acid isheated to the boiling point and maintained under reflux conditions forone hour. After this reaction i complete, the resultant solution isfiltered through a silica gel column to provide the 3-methoxyestra-1,3,5 (10),8,11-pentaen-17-one product which can be recrystallized frommethanol.

In a similar manner, by employing the C-3,17 substituted products ofExample 3 in the foregoing procedure, there are prepared thecorresponding 1,3,5 (10),8,11- pentaene, products, i.e.3-methoxyestra-l,3,5(10),8,11- pentaen 175 ol,3-methoxy-17a-methyl-1,3,5(10),8,11- pentaen 175 ol, 3 methoxy 17aethylestra-1,3, 5(10),8,11 pentaen 175 ol, 3methoxy-lh-ethynylestra-1,3,5(10),8,11-pentaen-175-ol, and so forth.

EXAMPLE 6 The procedure of Example 1 is repeated utilizing the followinginert liquid organic reaction media in lieu of benzene with similarresults in each instance.

toluene dioxane mestylene diethyl ether tetrahydrofuran diglyme Theforegoing procedures are prepared conducting the reaction at atemperature of instead of room temperature, with similar results in eachinstance.

EXAMPLE 7 The procedure of Example 2 is repeated utilizing, in lieu ofaqueous dioxane, aqueous solutions of the inert liquid reaction mediaset forth in the previous example, with similar results in eachinstance.

The foregoing procedures are repeated employing a temperature of 5instead of room temperature, with similar results in each instance.

EXAMPLE 8 The procedure of Example 3 is repeated utilizing, in lieu ofacidic methanolic dioxane, acidic methanolic solutions of the inertliquid reaction media set forth in the previous example, with similarresults in each instance.

EXAMPLE 9 The procedure of Example 3 is repeated using, in lieu ofacidic methanolic benzene, acidic 3% benzene solutions with the alkanolsof Column A, to prepare the corresponding 12ot-alkoxy product of ColumnB.

Ethanol 3-methoxy-l2a-ethoxyestra- 1,3,5 10) ,9-tetraene-17-one.

n-Propanol 3-methoxy-12a-n-propoxyestra- 1,3,5 (10),9tetraene-17-one.

Isopropanol 3-methoxy-12a-isopropoxyestra- 1,3 ,5 10 ,9-tetraen- 17-one.

n-Butanol 3-methoxy-12a-n-butoxyestra- 1,3,5 10 ,9-tetraen- 17-one.

The foregoing procedures are repeated employing a temperature of 35instead of room temperature, with similar results in each instance.

EXAMPLE 10 The procedures of Examples 4 and 5 are repeated utilizing, inlieu of oxalic acid, the following dilute acids, with similar results ineach instance.

acetic acid propionic acid maleic acid 2.5% hydrogen chloride inchloroform The foregoing procedures are conducted at 50 C. instead ofreflux, with similar results in each instance.

EXAMPLE 11 The procedures of Examples 1, 2, and 3 are repeatedutilizing, in lieu of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, thefollowing benzoquinones with similar results in each instance.

tetrachloro-1,2-benzoquinone 2,3-difluoro-1,4-benzoquinone2,3-dicyano-1,4-benzoquinoue 2,3-dibenzoyl-1,4-benzoquinone EXAMPLE 12In accordance with the foregoing methods, the following are prepared.

3-methoxyestra-1,3,5(10),8,1l-pentaen-175-ol,

Estra-1,3,5(10),8,11-pentaene-3,l75-dio1,

3,175 diacetoxyestra-l7a-methylacetoxy-1,3,5 10),8, 1 l-pentaene,

3 methoxy-17a-ethyny1-175-tetrahydropyran-2'-yloxy-3,17fl-bis(tetrahydrofuran-2-yloxy) 12a n pentoxy-17ozvinylestra-1,3,5(10),9( 1 1 -tetraene,

3 methoxy12a-n-hexyloxy-l7a-ethyl-17fl-propionyloxyestra-1,3,5,(10),9(11)-tetraene,

3 methoxy IZa-methoxy-l7a-propenyl-l7fi-acetoxy- 'estra-1,3,5( 10) ,9 11 )-tetraene, and

3 methoxy l2a-methoxy-l7a-n-propyl-l75-acetoxyestra-1,3,5(10),9(l1)-tetraene.

EXAMPLE 13 3 methoxyestra-1,3,5 (10),8,1l-pentaen-17-one (50 mg.) isdispersed in 10 ml. of toluene containing 10 mg. of 10% palladium oncarbon catalyst. The reaction mixture is refluxed for two hours andcooled to room temperature. The resultant mixture is kept under ahydrogen atmosphere overnight with stirring. The resultant mixture issubjected to preparative thin layer chromatography on silica gelimpregnated with silver nitrate to provide the 3-methoxyestra-l,3,5 10),6,8-pentaenel7B-one product.

In accordance with the foregoing procedure, the other1,3,5(l),8,11-pentaene compounds prepared in Examples 1 to 12 aresimilarly converted to the corresponding 1,3, ),6,8-pentaene products,namely,

3-methoxyestral ,3,5( 10 ,6, 8-pentaen-1 7 5M,3-methoXy-17a-methylestra-1,3 ,5( 10 ,6,8-pentaen- 175-01,3-methoxy-17a-ethylestra-1,3,5( 10) ,6,8-pentaen-17;3-ol,3-methoxy-17a-ethynylestra- 1,3 ,5 10) ,6,8-pentaen- 175-01,

estra- 1 ,3,5'( 10 ,6,8-pentane-3, l7B-diol,3,17B-diacetoxy-17u-methylestra-1,3 ,5 10) ,6,8-pentaene,

and so forth.

EXAMPLE 14 3 methoxyestra 1,3,5 (10),9(1l)-tetraene-12a-ol-17- one mg.)is dispersed in 100 ml. of ethyl acetate containing 5 mg. of platinumoxide and the resultant mixture kept under a hydrogen atmosphereovernight with stirring. The resultant mixture is subjected topreparative thin layer chromatography to provide the3-methoxyestra-1,3,5 10)-triene-12a-0l-17-one product.

The foregoing procedure can be practiced upon the other 12a-hydroxycompounds prepared above as well as the corresponding 12a-alkoxycompounds prepared as described above, to prepare the corresponding12a-hydroxyand -alkoxy-1,3,5(10)-triene products.

What is claimed is:

l. A compound selected from the group of compounds represented by theformulas:

wherein (III) R is hydrogen or lower alkyl;

R is hydroxy or a conventional ester or ether thereof;

R is hydroxy or a conventional ester or ether thereof;

R is hydrogen, alkyl of 1 to 3 carbon atoms, alkenyl of 1 to 3 carbonatoms, or alkynyl of 1 to 3 carbon atoms;

R" and R taken together are an oxo group.

2. A compound selected from those of Formula II of claim 1.

3. A compound selected from those of claim 2 wherein R is hydrogen ormethyl.

4. A compound selected from those of claim 3 wherein R is methoxy and Rand R taken together are an oxo group.

5. A compound selected from those of claim 3 wherein R is methoxy, R ishydroxy, and R is hydrogen.

6. A compound selected from those of claim 3 wherein R is methoxy, R ishydroxy, and R is methyl.

7. A compound selected from those of claim 3 wherein R is methoxy, R ishydroxy, and R is ethyl.

8. A compound selected from those of claim 3 wherein R is methoxy, R ishydroxy, and R is ethynyl.

9. A compound selected from those of Formula III of claim 1.

10. A compound selected from those of claim 9 wherein R is methoxy and Rand R taken together are an oxo group.

11. A compound selected from those of claim 9 wherein R is methoxy, R ishydroxy, and R is hydrogen.

12. A compound selected from those of claim 9 wherein R is methoxy, R ishydroxy, and R is methyl.

13. A compound selected from those of claim 9 wherein R is methoxy, R ishydroxy, and R is ethyl.

14. A compound selected from those of claim 9 where in R is methoxy, Ris hydroxy, and R is ethynyl.

15. A process which comprises treating an estra-1,3, 5(l0),9(11)-tetraene with a benzoquinone to prepare the correspondingestra-l,3,5(10),8,11-pentaene.

16. A process of claim 15 conducted in inert liquid organic reactionmedia and at a temperature of from 0 to 50.

17. A process of claim 16 conducted under anhydrous conditions.

18. A process of claim 15 conducted under aqueous conditions to preparethe corresponding 12u-hydroxyestra-l,3,5(10),9(11)-tetraene in additionto the estra-1,3, 5 (10),8,11-pentaene.

19. A process of claim 18 including the additional step of convertingthe 12a-hyroxyestra-1,3,5(10),9(11)-tetraene to the correspondingestra-1,3,5(10),8,11-pentaene with dilute acid.

20. A process of claim 15 conducted under acidic conditions in thepresence of a primary or secondary lower alkanol to prepare thecorresponding IZa-IOWGI alkoxyestra-1,3,5 (10),9(11)-tetraene inaddition to the estra-l, 3,5(10),8,l1-pentaene.

21. A process of claim 20 including the aditional step of converting theIZa-IOWCI alkoxyestra-1,3,5(10),9(11)- tetraene to the correspondingestra-1,3,5 (10),8,l1-pentaene with dilute acid.

22. A process of claim 15 wherein said benzoquinone is selected from thegroup consisting of tetrachloro-l,2-benzoquinone,2,3-difluoro-1,4-benzoquinone, 2,3-dicyano-1, 4-benzoquinone,2,3-dibenzoyl-1,4-benzoquinone, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

23. A process of claim 22 wherein said benzoquinone is2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

24. A process which comprises treating an estra-1,3,5(l0),9(ll)-tetraene with a benzoquinone to prepare the correspondingestra-1,3,5(10),8,1l-pentaene and dehydrogenating the latter withpalladium catalyst followed by hydrogenation to give the correspondingestra-1,3,5 (10), 6,8-pentaene.

References Cited UNITED STATES PATENTS 3,476,780 11/1969 Smith et al260-397.3

3,536,736 10/1970 Diassi 260-397.45

ELBERT L. ROBERTS, Primary Examiner U.S. c1. X.R. 260-397.5, 239.55

